“Antimicrobial utilization in a paediatric intensive care unit in India: A step towards strengthening antimicrobial stewardship practices"

Antimicrobials are frequently used in critically ill children admitted to the Paediatric Intensive Care Unit (PICU). The antimicrobial use data from Indian PICUs is limited using standard metrics such as Days of therapy (DOT). This study aimed to determine the baseline trend of antimicrobial use in PICU of a tertiary care teaching hospital of Raipur district of Chhattisgarh, India using standard metrics with the goal of developing facility-wide antibiotic policy and strengthening the antimicrobial stewardship activities. This active surveillance was conducted over a period of 18 months, from November 1, 2019, to March 21, 2021, in patients aged one month to 14 years who were admitted for ≥ 48 hours to the PICU at a tertiary care teaching hospital of Raipur District. Data on patient characteristics, antimicrobial indications, antimicrobial prescription information, and clinical outcomes were collected using pre-designed data abstraction forms. The descriptive statistic was used to represent the results. The antimicrobial consumption was analyzed according to the WHO AWaRe Class (Access, Watch, and Reserve groups) of antibiotics. The antimicrobial consumption was expressed as DOT/1000 patient-days (PD). A total of 216 patients were surveyed during the study period. The average number of antimicrobials prescribed per hospitalisation was 2.60 (range: 1–12), with 97.22% administered via parenteral route. Overall, DOT/1000-PD was 1318. The consumption of Watch Group antimicrobials was highest with 949 DOT/1000-PD, followed by Access (215) and Reserve Group (154), respectively. Ceftriaxone (208 DOT/1000 PD) was the most commonly prescribed antimicrobial agent, followed by Vancomycin (201), Meropenem (175), Piperacillin-Tazobactam (122) and Colistin (91). The patients who were escalated (28.24%) from empirical antimicrobial therapy had longer median PICU stay (8 days) compared those who were de-escalated (23.6%). Targeted therapy was given in 10.2% patients. The overall mortality rate was 14.35% and was higher (29.3%) in patients in whom empirical therapy was escalated compared to those who were de-escalated or continued. The study established a benchmark for antimicrobials use in the PICU and highlighted priority areas for antimicrobial stewardship intervention to enhance de-escalation rates, enhance targeted therapy, and reduce the overuse of antimicrobials especially belonging to the reserve group.

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Ethics Committee approval and the consent waiver was obtained before initiating the surveillance (AIIMSRPR/IEC/2019/331) from Institute Ethics Committee.The patient identity was not revealed at any stage during and after the study.The privacy and confidentiality have been maintained.Yes -all data are fully available without restriction  These authors contributed equally to acquisition of clinical data and data interpretation.

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 These authors contributed equally to acquisition of clinical data.

patient-days (PD).
A total of 216 patients were surveyed during the study period.The average number of antimicrobials prescribed per hospitalisation was 2.60 (range: 1 -12), with 97.22% administered via parenteral route.Overall, DOT/1000-PD was 1318.The consumption of Watch Group antimicrobials was highest with 949 DOT/1000-PD, followed by Access (215) and Reserve Group (154), respectively.Ceftriaxone (208 DOT/1000 PD) was the most commonly prescribed antimicrobial agent, followed by Vancomycin (201), Meropenem (175), Piperacillin-Tazobactam (122) and Colistin (91).The patients who were escalated (28.24%) from empirical antimicrobial therapy had longer median PICU stay (8 days) compared those who were de-escalated (23.6%).Targeted therapy was given in 10.2% patients.The overall mortality rate was 14.35% and was higher (29.3%) in patients in whom empirical therapy was escalated compared to those who were de-escalated or continued.
The study established a benchmark for antimicrobials use in the PICU and highlighted priority areas for antimicrobial stewardship intervention to enhance de-escalation rates, enhance targeted therapy, and reduce the overuse of antimicrobials from the reserve group.

Introduction
According to World Health Organization (WHO), irrational antibiotic use contributes to antimicrobial-resistance (AMR) worldwide.In South-East Asia, antibiotic misuse is common and contributes to antimicrobial resistance. 1 Broad-spectrum antimicrobials can cause infections due to multi-drug-resistant gram-negative bacilli and invasive candidiasis. 2,3Multidrug-resistant organism (MDRO) infections increase healthcare costs, length of stay, Intensive care unit (ICU) admission, morbidity, and mortality. 2,4-6A WHO-funded community-based survey in India found that up to 53% of public sector primary care patients and 70% of private sector patients receive antibiotics for upper respiratory tract infection and acute diarrhoea in children and adults, indicating overuse and inappropriate use. 7ediatric patients are special population, therefore inappropriate antimicrobial use that causes AMR is a major concern.10] Antimicrobials are widely used in PICUs (67%-97%) due to empirical antimicrobial therapy. 11Empirical antimicrobial therapy often begins with local susceptibility.However, signs, symptoms, and severity of the infection must be assessed and antimicrobial therapy narrowed for common ICU infections. 12A lack of culture-sensitivity reports, a deteriorating patient's clinical status, or a failure to communicate between clinicians or residents on clinical rounds often lead clinicians to escalate and change antimicrobials during empirical antimicrobial therapy. 13to the massive AMR problem, focused and coordinated efforts to improve rational antimicrobial prescribing and active AMR surveillance through the Antimicrobial Stewardship Programme (AMSP) are needed.AMSP that has been successfully implemented in adults can also be implemented for paediatric populations.Studies by J R Paño-Pardo et al. 14 , J Y Ting et al. 15 , and Jef Willems et al. 16

Materials and methods
The active surveillance was conducted over 18 months (from November 1, 2019 to

Statistical analysis
Microsoft Excel 2013 were used to interpret the data for descriptive statistics such as median and interquartile range.Discrete data was expressed as counts or percentages.The antimicrobial consumption was expressed as DOT/1000 patient-days.

Results
The study included 216 of 511 screened patients who met inclusion and exclusion criteria.At the end of the surveillance period, the total number of patient -days was 2212.(Fig The patients had a median age of four years (IQR: 0.62 -9.00). .S1) Empirical antimicrobial therapy was de-escalated in 23.6% of patients, 17.6% of whom had microbiological culture-sensitivity reports.Based on culture-sensitivity, 11.1% of patients had empirical antimicrobial therapy de-escalated, escalated, or continued.

4.
Incidence Rate of Hospital-acquired MRSA infection per 1000 patient days @ 0.9

5.
Incidence Rate of Total Hospital-acquired Multi drug resistant organism (MDRO) infection per 1000 patient days @ 6.3 yield, critical illness, risk of MDRO infections, and non-improvement or clinical deterioration. 22prevalence of high antimicrobial use in paediatric patients in Southeast Asian countries is comparable to India and Western countries.In a study from Pakistan, Abbas et al. 11 (2016) found that 100% of PICU-admitted patients received at least one antimicrobial agent for prophylaxis, therapeutic, or empirical purposes.Similarly, Boone et al. 23 (2020) noted that antimicrobials were prescribed in 73% of infants admitted to hospitals in Bangladesh.

Conclusion
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with the following details: Initials of the authors who received each award • Grant numbers awarded to each author • The full name of each funder • URL of each funder website • Did the sponsors or funders play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript?• Did you receive funding for this work?Competing Interests Use the instructions below to enter a competing interest statement for this submission.On behalf of all authors, disclose any competing interests that could be perceived to bias this work-acknowledging all financial support and any other relevant financial or nonfinancial competing interests.This statement is required for submission and will appear in the published article if the submission is accepted.Please make sure it is accurate and that any funding sources listed in your Funding Information later in the submission form are also declared in your Financial Disclosure statement.View published research articles fromThe authors have declared that no competing interests exist.Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationEnter: The authors have declared that no competing interests exist.Authors with competing interestsEnter competing interest details beginning with this statement: I have read the journal's policy and the authors of this manuscript have the following competing interests: [insert competing interests here] /A" if the submission does not require an ethics statement.

Format
for specific study types Human Subject Research (involving human participants and/or tissue) Give the name of the institutional review board or ethics committee that approved the study • Include the approval number and/or a statement indicating approval of this research • Indicate the form of consent obtained (written/oral) or the reason that consent was not obtained (e.g. the data were analyzed anonymously) • Animal Research (involving vertebrate animals, embryos or tissues) Provide the name of the Institutional Animal Care and Use Committee (IACUC) or other relevant ethics board that reviewed the study protocol, and indicate whether they approved this research or granted a formal waiver of ethical approval • Include an approval number if one was obtained • If the study involved non-human primates, add additional details about animal welfare and steps taken to ameliorate suffering • If anesthesia, euthanasia, or any kind of animal sacrifice is part of the study, include briefly which substances and/or methods were applied • Field Research Include the following details if this study involves the collection of plant, animal, or other materials from a natural setting: Field permit number • Name of the institution or relevant body that granted permission • Data Availability Authors are required to make all data underlying the findings described fully available, without restriction, and from the time of publication.PLOS allows rare exceptions to address legal and ethical concerns.See the PLOS Data Policy and FAQ for detailed information.
have shown successful implementation of AMSP in paediatric settings.AMSP implementation requires baseline antimicrobial use and resistance patterns from our patient care areas.Antimicrobial use in children, especially in PICUs, is poorly documented.Upon reviewing the relevant literature, no Indian study has evaluated the use of antimicrobials in PICUs using standard metrics like Days of Therapy.Both antimicrobial use and clinical outcomes in PICU patients can provide insight.Thus, we designed this surveillance study to assess antimicrobial use and clinical outcomes in PICU-admitted patients receiving antimicrobial therapy.

April 30 ,
2021) in Paediatric Intensive Care Unit (PICU) of All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, India.Ethics Committee approval and the consent waiver was obtained before initiating the surveillance (AIIMSRPR/IEC/2019/331) from Institute Ethics Committee.The patient identity was not revealed at any stage during and after the study.The privacy and confidentiality have been maintained.All the admitted patients aged one month to fourteen years in PICU, receiving at least one or more antibacterial agents with or without antifungal agents and whose PICU stay was ≥ 48 hours were included.Patients who received only antitubercular, antifungal, or antiviral agents, topical antimicrobial agents, or who were discharged, left against medical advice (LAMA), or who died within 48 hours of admission were excluded.Active surveillance was conducted in the PICU every day between 11:00 AM and 1:00 PM.The data were collected using a pre-designed structured data abstraction form from the patients' health records, nursing charts and microbiology laboratory reports.The information collected comprise of antimicrobial agents given by system route (oral or parenteral), microbiological samples sent and their culture sensitivity reports, laboratory investigations, and patient-days.The patientdays were counted every day at 11 AM during the surveillance period and it included patients admitted to the PICU on or before 11:00 AM on the day of data collection.(Fig 1)

Fig 1 .
Fig 1. Flow of the study participants

Fig 2 .
Fig 2. Data showing percentage of patients who received multiple drug coverage for

Fig 3 .
Fig 3. Box and Whisker plot for PICU stay by number of patients in whom antimicrobial

Fig 4 .
Fig 4. Relationship between mortality rate and escalation, de-escalation and continuation conclusion, this surveillance study has provided valuable baseline data on antimicrobial usage in a PICU of a tertiary care hospital in Chhattisgarh State.This data can serve as a benchmark for other hospitals in the state and in India to compare their antimicrobial usage in pre-and post-AMSP intervention period.In addition, this surveillance identified check-points for stewardship interventions, such as reducing double anaerobic coverage and improving culture-positivity yield, facilitating de-escalation and targeted therapy, reducing overuse of reserve group antimicrobials, impacting clinical outcomes like mortality and length of stay.

Figure 3 .
Figure 3. Box and Whisker plot for PICU stay by number of patients in whom antimicrobial therapy was escalated, de-escalated and continue

Figure 4 .
Figure 4. Relationship between mortality rate and escalation, de-escalation and continuation Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation

Table 1 . Demographic Details and Clinical Characteristics.
Table 1 depicts the demographic and clinical characteristics of the patients.

Table 4 . Clinical and Microbiological Indicators.
33uble Gram-negative and anaerobic coverage (DAC) was another finding in our surveillance.Song et al.24 (2015)found that 26.8% of patients received unnecessary double anaerobic coverage for over three days, compared to 20.8% in our study.In contrast, Regular review of hospital formulary and alignment with the National Essential Medicine List can ensure the availability of narrow-spectrum antimicrobials for targeted drug therapy.The low culture-positivity yield in a critical care setting can be attributed to several factors.These include the lack of sampling before initiating antimicrobial therapy, improper Healthcare Safety Network (NHSN) offers an automated model for monthly DOT data collection.33Aligningwith ICMR's initiative, a national network in India can provide baseline data for stewardship evaluation.